Background: Novel HER2 antibody-drug conjugates have demonstrated clinical benefit in breast cancer with HER2 IHC scores 1+ or 2+/ISH negative. As a result, a new concept of HER2 low breast cancer has been proposed. The prognostic implications of this expression remain unclear. To determine whether HER2 low expression affects disease evolution in patients with endocrine receptor positive, HER2 negative breast cancer, we performed a retrospective analysis of patients treated with first line CDK4/6 inhibitors in our center. Methods: We conducted a search for patients who received first line CDK4/6 inhibitors plus endocrine therapy at Virgen del Rocio Hospital between June 2016 and September 2021. 175 subjects were selected and followed for 42 months. Patients were grouped according to HER2 expression: HER2 0+ and HER2 low (IHC 1+ or 2+/ISH negative). Clinical characteristics and PFS were then compared. Clinical characteristics were evaluated by descriptive analysis. Kaplan Meier curves were used to estimate PFS, and Breslow test to estimate p-value. Statistical analyses were performed with SPSS 28.0. Results: All patients were female and median age at treatment initiation was 61 years. 49 patients received abemaciclib, 83 palbociclib and 43 ribociclib. 49 patients were HER2 0+, 57 HER2 1+ and 69 HER2 2+. Key clinical and treatment characteristics are shown. Overall PFS was 35.61 months (95% CI 25.46 - 45.76). PFS was 21.52 months (95% CI: 14.30 - 28.73), 31.15 months (95% CI: 15.59 - 46.70) and 39.49 months (95% CI: not estimable) in the HER2 0+, 1+ and 2+ population, respectively. There was no difference between the three arms: HER2 0+ vs HER2 1+ p=0.881; HER2 0+ vs HER2 2+ p=0.155; HER2 1+ vs HER2 2+ p=0.238. No significant differences were observed when comparing the HER2 0+ cohort to the overall HER2 low population: p=0.347. Conclusions: In our cohort of patients with luminal phenotype breast cancer treated with CDK4/6 inhibitors, HER2 low expression was associated with a trend toward longer PFS, although no statistically significant differences were found.